Use of fumaric acid derivatives

ABSTRACT

Disclosed is a method of treating auto-immune diseases by the administration of certain fumaric acid monoalkyl esters as salts or free acids thereof either alone or in combination with a dialkyl fumarate.

This Application is a 371 of PCT/EP98/01894 filed Apr. 1, 1998 whichclaims priority from German Patent Application no. 197,21,099.5 filedMay 20, 1997.

BACKGROUND OF THE INVENTION

The present invention relates to the use of certain fumaric acidmonoalkyl esters as salt either alone or in combination with a dialkylfumarate for preparing pharmaceutical compositions for the treatment ofpoly-arthritis, multiple sclerosis and graft-versus-host reactions. Theinvention also relates to medicaments containing one or several fumaricacid monoalkyl esters in the form of free acids, optionally incombination with dialkyl fumarate, as active ingredient for thetreatment of polyarthritis, multiple sclerosis, graft-versus-hostreactions and other auto-immune diseases. These compositions do notcontain fumaric acid per se. The use according to the invention alsoextends to the treatment of juvenile diabetes, Hashimoto's thyroiditis,Grave's disease, systemic Lupus erythematosus (SLE), Sjogren's syndrome,pernicious anaemia and chronically active (=lupoid) hepatitis.

Pharmaceutical compositions which end in the citric acid cycle whendecomposed after administration or which belong to the citric acid cycleare increasingly gaining therapeutic value, especially when given inhigh dosages, because they help relieve or heal diseases withcryptogenetic causes.

Fumaric acid, for example, inhibits the growth of the Ehrlich ascitestumour in mice, reduces the toxic effects of mitomycin C and aflatoxin[K. Kuroda, M. Akao, Biochem. Pharmacol. 29, 2839-2844 (1980)/Gann. 72,777-782 (1981)/Cancer Res. 36, 1900-1903, (1976)] and displays aanti-psoriatic and anti-microbial activity [C. N. Huhtsnen, J. Food Sci.48, 1574 (1983)/M. N. Islam, U.S. Pat. No. 4,346,118 dated Aug. 24,1982/C. A. 97, 161317b (1982)].

When administered parenterally, dermally and especially perorally, highdosages of fumaric acids or its derivatives known so far such asdihydroxy fumaric acid, fumaramide and fumaronitrile have suchunacceptably severe side effects and high toxicity [P. Holland, R. G.White, Brit. Dermatol. 85, 259-263 (1971)/M. Hagedorn, K. W. Kalkoff, G.Kiefer, D. Baron. J. Hug, J. Petres, Arch. Derm. Res. 254, 67-73 (1975)]that, in most cases, such a therapy had to be abandoned in the past.

European Patent Application 18 87 49 already describes fumaric acidderivatives and pharmaceutical compositions containing the same for thetreatment of psoriasis. Pharmaceutical compositions for the treatment ofpsoriasis containing a mixture of fumaric acid and other fumaric acidderivatives are known from DE-A-25 30 372. The content of free fumaricacid is obligatory for these medicaments.

DE-A-26 21 214 describes medicaments containing the fumaric acidmonoethyl ester and its mineral salts as active ingredient for thetreatment of psoriasis. The publication “Hautarzt (Dermatologist) (1987)279-285” discusses the use of fumaric acid monoethyl ester salts (Ca,Zn, Mg) and of the fumaric acid dimethyl ester for the treatment ofpsoriasis. Pharmaceutical compositions containing a mixture of fumaricacid monoalkyl ester salts and a fumaric acid diester for the treatmentof psoriasis, psoriatic arthritis, neurodermitis and enteritisregionalis Crohn are known from EP 0 312 697 B1.

Surprisingly, we have now found in in vitro tests and in animalexperiments that it is possible to treat polyarthritis, multiplesclerosis and graft-versus-host reactions with pharmaceuticalcompositions using one or several compounds from the group consisting ofcalcium, magnesium, zinc and iron salts of fumaric acid monoalkyl estersof the general formula

optionally in admixture with dialkyl fumarate of the formula

 wherein A is a bivalent cation from the series consisting of Ca, Mg, Znor Fe or a monovalent cation from the series consisting of potassium orsodium, respectively, and n denotes the numeral 1 or 2 depending on thetype of cation,

optionally together with commonly used pharmaceutical excipients.

We also found an effect when polyarthritis, multiple sclerosis andgraft-versus-host reactions were treated with pharmaceuticalcompositions containing one or several compounds of alkyl hydrogenfumaric acid of the general formula

optionally in admixture with dialkyl fumarate of the formula

 wherein R, R₁, R₂ may be the same or different and each of R, R₁ and R₂is an alkyl group having 1 to 5 carbon atoms (C₁-C₅ alkyl);

and, optionally, commonly used pharmaceutical excipients and carriers.

Preferred compositions according to the invention contain the calciumsalt of the fumaric acid monomethyl ester, the calcium salt of thefumaric acid monomethyl ester in admixture with dimethyl fumarate or therelevant salts of the fumaric acid monoethyl ester.

Preparations containing the calcium salt of the fumaric acid monoalkylester or the fumaric acid alkyl ester in the form of the free acid in anamount of 10 to 300 mg are especially suitable for administration, thetotal weight of the active ingredients being 10 to 300 mg.

Other preferred oral forms of administration contain 10 to 290 parts byweight of the calcium salt of the fumaric acid monoalkyl ester and 290to 10 parts by weight of dimethyl fumarate as well as 1 to 50 parts byweight of the zinc salt of the fumaric acid monoalkyl ester or 1 to 250parts by weight of the calcium salt of the fumaric acid monoalkyl ester,250 to 10 parts by weight of dimethyl fumarate, 1 to 50 parts by weightof the magnesium salt of the fumaric acid monoalkyl ester and 1 to 50parts by weight of the zinc salt of the fumaric acid monoalkyl ester orthe monomethyl ester, respectively, the total weight of the activeingredients being 30 to 300 mg.

Preferred compositions according to the invention also contain themethyl hydrogen fumarate in an amount of 10 to 300 mg.

For commencement of a systemic therapy and, vice versa, termination ofthe treatment by gradual reduction of the dosage, low doses containing,for example, 30.0 mg of dimethyl fumarate, 20.0 mg of the calcium saltof monoethyl fumarate and 3.0 mg of the zinc salt of monoethyl fumarateor monomethyl fumarate, respectively, are advantageous.

For therapeutic dosing after an initial phase, for example, a dosage of120.0 mg of dimethyl fumarate, 87.0 mg of the calcium salt of themonoethyl fumarate and 3.0 mg of the zinc salt of the mono ethylfumarate or the monomethyl fumarate may be used.

The fumaric acid derivatives contained in the compositions according tothe invention, are obtained by

a) condensation of a compound of the formula

 with 2 moles of alkyl alcohol (ROH) by a known method to obtain adiester, followed by controlled hydrolysation to obtain a monoester, or

b) condensation of 1 mole of the relevant alkyl alcohol (ROH) in theusual manner followed by hydrolysis of the monoacid chloride thusobtained to obtain an acid, or

c) direct condensation of the fumaric acid with 2 moles of alkyl alcohol(ROH) by a known method to obtain the relevant diester followed bycontrolled hydrolysation to obtain the monoester, or

d) direct condensation of maleic acid or maleic anhydride with 1-2 molesof the relevant alkyl alcohol (ROH) by a known method to obtain a mono-or diester followed by catalytic isomerisation to obtain the respectivefumaric acid derivative.

The salts of the fumaric acid monoalkyl esters may also be obtained byreacting a compound of the general formula

wherein R is a C₁-C₅ alkyl group with equivalent mole amounts of Na, K,Fe, Ca, Mg or Zn hydroxide or oxide in toluene and removing the watergenerated during the reaction.

For particularly preferred applications, preparations containing thefollowing active ingredients in the stated dosages and proportions areused:

as a pharmaceutical composition for oral administration in the form oftablets or capsules, characterised in that they contain the calcium saltof the fumaric acid monomethyl ester in an amount of 10 to 300 mg, thetotal weight of the active ingredients being 10 to 300 mg; or

as a pharmaceutical composition for oral administration in the form oftablets or capsules, characterised in that they contain 10 to 290 partsby weight of the calcium salt of the fumaric acid monomethyl ester and290 to 10 parts by weight of dimethyl fumarate, the total weight of theactive ingredients being 20 to 300 mg; or

additionally, as a pharmaceutical composition for oral administration inthe form of tablets or capsules characterised in that they contain 10 to250 parts by weight of the calcium salt of the fumaric acid monomethylester, 1 to 50 parts by weight of dimethyl fumarate and 1 to 50 parts byweight of the zinc salt of the fumaric acid monomethyl ester, the totalweight of the active ingredients being 20 to 300 mg, or as apharmaceutical composition for oral administration in the form oftablets or capsules, characterised in that they contain 10 to 250 partsby weight of the calcium salt of the fumaric acid mono methyl ester, 250to 10 parts by weight of dimethyl fumarate, 1 to 50 parts by weight ofthe magnesium salt of the fumaric acid monomethyl ester and 1 to 50parts by weight of the zinc salt of the fumaric acid monomethyl ester,the total weight of the active ingredients being 30 to 300 mg, or,alternatively,

as a pharmaceutical composition for oral administration which may beprovided with a coating resistant to gastric acid,

as a pharmaceutical preparation for the treatment of polyarthritis,multiple sclerosis or graft-versus-host reactions for peroraladministration in the form of pellets, micro-tablets, capsules, granulesand tablets, in the form of ointments, plasters or lotions for cutaneousand transdermal administration, in the form of aqueousmicro-dispersions, oil-in-water emulsions or oily solutions forparenteral administration, or suppositories or micro-enemas for rectaladministration, and

as a pharmaceutical composition for the treatment of polyarthritis,multiple sclerosis or graft-versus-host reactions, characterised in thatit contains one or several compounds selected from the group consistingof free acids of fumaric acid monoalkyl esters of the general formula

optionally in combination with dialkyl fumarate of the formula

 and R, R₁ and R₂ are as defined above.

and carriers, said composition not containing fumaric acid in its freeform, or

as a pharmaceutical composition for oral administration in the form oftablets, capsules or micro-tablets, characterised in that they containalkyl hydrogen fumarate in an amount of 10 to 300 mg, the total weightof the active ingredients being 10 to 300 mg, or

as a pharmaceutical composition for oral administration in the form oftablets, capsules or micro-tablets, characterised in that they contain10 to 290 parts by weight of alkyl hydrogen fumarate and 290 to 10 partsby weight of dialkyl fumarate, the total weight of the activeingredients being 20 to 300 mg, or as pharmaceutical compositionscontaining the free acid of the fumaric acid monomethyl ester (methylhydrogen fumarate), or

as a pharmaceutical composition for oral administration in the form oftablets, capsules or micro-tablets, characterised in that they eachcontain the methyl hydrogen fumarate in an amount of 10 to 300 mg, thetotal weight of the active ingredients being 10 to 300 mg,

or as a pharmaceutical composition for oral administration in the formof tablets, capsules or micro-tablets containing 10 to 290 parts byweight of methyl hydrogen fumarate and 290 to 10 parts by weight ofdimethyl fumarate, the total weight of the active ingredients being 20to 300 mg, or,

as a pharmaceutical composition for the treatment of polyarthritis,multiple sclerosis or graft-versus-host reactions for peroraladministration in the form of micro-pellets, micro-tablets, capsules,granulates and tablets, in the form of ointments, plasters, lotions orshower preparations for cutaneous and transdermal administration, in theform of aqueous micro-dispersions, oil-in-water emulsion or oilysolutions for parenteral administration, or suppositories ormicro-enemas for rectal administration.

According to a preferred form of administration, the size or meandiameter of the pellets or micro-tablets is in the range of 300 to 2,000μm, especially in the range of 500 μm to 1,500 μm or 1,000 μm.

Another special benefit of the use according to the invention is toalternate a treatment regimen with cyclosporin sequentially withadministration of the fumaric acid derivatives described above. In otherwords, an application of fumaric acid derivatives according to the abovedefinitions for a period of one or several weeks could follow acyclosporin therapy extending over one or several weeks. As a result,the well-known severe side effects of a long-term cyclosporin therapycan be reduced dramatically and unexpectedly.

In order to illustrate the use according to the invention, variousexamples for the preparation of preferred medicaments are given below:

PRODUCTION EXAMPLES Example 1 Production of enteric-coated film tabletscontaining 100.0 mg of monoethyl fumarate-Ca salt, which corresponds to71 mg of fumaric acid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 10.000 kg of monoethyl fumarate-Ca salt are crushed,mixed intensely and homogenised by means of an 800 sieve. Then anexcipient mixture of the following composition is prepared: 21.000 kg ofstarch derivative (STA-RX 1500®), 2.000 kg of micro-crystallinecellulose (Avicel PH 101®), 0.600 kg of polyvinyl pyrrolidone (PVP,Kollidon® 25), 4.000 kg of Primogel®, 0.300 kg of colloidal silicic acid(Aerosil®).

The active ingredient is added to the entire powder mixture, mixed,homogenised by means of a 200 sieve and processed with a 2% aqueoussolution of polyvinyl pyrrolidone (PVP, Kollidon® 25) in the usualmanner into binder granules, and then mixed with the outer phase in adry state. The latter consists of 2.000 kg of a so-called FST complexcontaining 80% of talcum, 10% of silicic acid and 10% of magnesiumstearate.

Afterwards the mixture is pressed into convex tablets with a weight of400 mg and a diameter of 10.0 mm by the usual method. Instead of theseclassic compaction methods, other methods such as direct compaction orsolid dispersions according to the melting and spray drying method mayalso be used for preparing tablets.

Enteric Coating

A solution of 2.250 kg of hydroxy propyl methyl cellulose phthalate(HPMCP, Pharmacoat HP® 50) is dissolved in a solvent mixture consistingof 2.50 liters of demineralised water, 13.00 liters of acetone (Ph.Helv. VII) and 13.00 liters of ethanol (94% by weight) and then 0.240 kgof castor oil (Ph. Eur. II) added to the solution. The solution ispoured or sprayed in portions onto the tablet cores in a coating pan ina conventional manner or applied by means of a fluidised bed apparatusof the appropriate structure.

After drying, the film coating is applied. Said coating consists of asolution of Eudragit E 12.5%® 4.800 kg, talcum (Ph. Eur. II) 0.340 kg,titanium(VI) oxide Cronus RN 56® 0.520 kg, coloured lacquer ZLT-2 blue(Siegle) 0.210 kg, and polyethylene glycol 6000 (Ph. Helv. VII) 0.120 kgin a solvent mixture of 8.200 kg of 2-propanol (Ph. Helv. VII), 0.060 kgof glycerine triacetate (Triacetin®) and 0.200 kg of demineralisedwater. After homogenous distribution in the coating pan or the fluidisedbed, the mixture is dried and polished in the usual manner.

Example 2 Preparation of enteric coated capsules containing 86.5 mg ofmonoethyl fumarate-Ca salt and 110.0 mg of dimethyl fumarate, whichcorresponds to a total of 150 mg of fumaric acid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 8.650 kg of monoethyl fumarate-Ca salt and 11.000 kg ofdimethyl fumarate are intensely mixed with a mixture consisting of15.000 kg of starch, 6.000 kg of lactose (Ph. Helv. VII), 2.000 kg ofmicro-crystalline cellulose (Avicel®), 1.000 kg of polyvinyl pyrrolidone(Kollidon® 25) and 4.000 kg of Primogel® and homogenised by means of a800 sieve.

Together with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon®25) the entire powder mixture is processed in the usual manner into abinder granulate and mixed with the outer phase in the dried state. Saidouter phase consists of 0.350 kg of colloidal silicic acid (Aerosil®),0.500 kg of Mg stearate and 1.500 kg of talcum (Ph. Helv. VII). Thehomogeneous mixture is then filled in portions of 500.0 mg intoappropriate capsules which are then provided with a enteric-coatedcoating consisting of hydroxy propyl methyl cellulose stearate andcastor oil as softening agent by a known method. Instead of hardgelatine capsules, the mixture may also be filled into appropriategastric acid-resistant capsules, which consist of a mixture of celluloseacetate phthalate (CAP) and hydroxy propyl ethyl cellulose phthalate(HPMCP).

Example 3 Preparation of enteric-coated capsules containing 203.0 mg ofmonoethyl fumarate-Ca salt, 5.0 mg of monoethyl fumarate-Mg salt and 3.0mg of monoethyl fumarate-Zn salt, which corresponds to a total of 150 mgof fumaric acid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 20.300 kg of mono ethyl fumarate-Ca salt, 0.500 kg ofmonoethyl fumarate-Mg salt and 0.300 kg of monoethyl fumarate-Zn saltare crushed, mixed intensely and homogenised using an 800 sieve. Ahomogenous powder mixture of the following composition is mixed intothis active ingredient mixture: spray-dried lactose 12.900 kg, colloidalsilicic acid 1.000 kg, micro-crystalline cellulose (Avicel®) 2.000 kg,magnesium stearate (Ph. Helv. VII) 1.000 kg and talcum (Ph. Helv. VII)2.000 kg. The entire powder mixture is homogenised once again by meansof a 200 sieve, filled into hard gelatine capsules with a net weight of400 mg and sealed. The application of a gastric acid-resistant coatingis carried out in accordance with example 2.

Example 4 Preparation of enteric-coated micro-tablets in capsulescontaining 87.0 mg of monoethyl fumarate-Ca salt, 120.0 mg of dimethylfumarate, 5.0 mg of monoethyl fumarate-Mg salt and 3.0 mg of monoethylfumarate-Zn salt, which corresponds to a total of 164 mg of fumaric acid(“forte” tablets)

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 8.700 kg of monoethyl fumarate-Ca salt, 12.000 kg ofdimethyl fumarate, 0.500 kg of monoethyl fumarate-Mg salt and 0.30 kg ofmonoethyl fumarate-Zn salt are crushed, intensely mixed and homogenisedby means of an 800 sieve. Then an excipient mixture of the followingcomposition is prepared: 18.00 kg of starch derivative (STA-RX 1500),0.30 kg of micro-crystalline cellulose (Avicel PH 101), 0.75 kg of PVP(Kollidon 120)., 4.00 kg of Primogel, 0.25 kg of colloidal silicic acid(Aerosil). The entire powder mixture is added to the active ingredientmixture, homogenised by means of a 200 sieve, processed in the usualmanner with a 2% aqueous solution of polyvinyl pyrrolidone (KollidonK25) to obtain a binder granulate and mixed in a dry state with theouter phase consisting of 0.50 kg of Mg stearate and 1.50 kg of talcum.Then the powder mixture is pressed by the conventional method intoconvex micro-tablets with a gross mass of 10.0 mg and a diameter of 2.0mm. Instead of this classic tabletting method other methods for makingtablets such as direct tabletting or solid dispersions by the meltmethod and the spray drying method may also be used.

The gastric acid-resistant coating may be poured or sprayed on in aclassic coating pan or applied in a fluidised-bed apparatus. In order toachieve resistance to gastric acid, portions of a solution of 2.250 kgof hydroxy propyl methyl cellulose phthalate (HPMCP, Pharmacoat HP 50)are dissolved in a mixture of the following solvents: acetone 13.00 l,ethanol 94% weight denatured with 2% ketone 13.50 l and demineralisedwater 2.50 l. 0.240 kg of castor oil are added as softening agent to thefinished solution and applied in portions to the tablet cores in theusual manner.

Film-coat: After drying is completed, a suspension of the followingcomposition is applied as a film-coat in the same apparatus: talcum0.340 kg, titanium (VI) oxide Cronus RN 56 0.400 kg, coloured lacquer Lred lacquer 86837 0.324 kg, Eudragit E 12.5% 4.800 kg and polyethyleneglycol 6000 pH 11 XI 0.120 kg in a solvent mixture of the followingcomposition: 2-propanol 8.170 kg, aqua demineralisata 0.200 kg andglycerine triacetate (Triacetin) 0.600 kg.

The gastric acid-resistant micro-tablets are then filled into hardgelatine capsules at a net weight of 500.0 mg and sealed.

Example 5 Preparation of enteric-coated film tablets containing 67.0 mgof monoethyl fumarate-Ca salt, 30.0 mg of dimethyl fumarate, 5.0 mg ofmonoethyl fumarate-Mg salt and 3.0 mg of monoethyl fumarate-Zn salt,which corresponds to 75 mg of fumaric acids (“mite” tablets)

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 3.000 kg of dimethyl fumarate, 6.700 kg of monoethylfumarate-Ca salt, 0.500 kg of monoethyl fumarate-Mg salt and 0,300 kg ofmonoethyl fumarate-Zn salt are homogenised by means of an 800 sieve. Anexcipient mixture of the following composition is prepared in a similarmanner to example 4, namely 30.000 kg of starch derivative (STA-RX1500®), 3.000 kg of micro-crystalline cellulose (Avicel PH 101), 0.750kg of polyvinyl pyrrolidone (PVP, Kollidon® 25), 4.000 kg of Primogel,0.250 kg of colloidal silicic acid (Aerosil®). The excipients and themixture of active ingredients are mixed intimately and homogenised bymeans of a 200 sieve. With the aid of a 2% aqueous solution of polyvinylpyrrolidone (PVP, Kollidon® 25), the mass is processed in the usualmanner to obtain a binder granulate. A powder mixture of the followingexcipients is added to the dried granulate as an outer phase: 0.500 kgof Mg stearate (Ph. Eur.) and 0.800 kg of talcum (Ph. Eur. II).

The homogenous granulate mixture is pressed in the usual manner toobtain convex tablet cores having a weight of 500.0 mg and a diameter of11.5 mm. In addition to binder methods other tabletting methodsaccording to examples 1 and 4 may also be used. The application of agastric acid-resistant coating and a film-coat to the tablet cores isdescribed analogously in examples 1 and 4.

The compositions according to the invention are preferably administeredperorally in the form of tablets or capsules. These solid single-dosagemedicaments are preferably provided with a gastric acid-resistantcoating which, once having passed the stomach, is dissolved within a fewminutes by the juice present in the small intestine and releases theactive ingredient from the medicament. At the beginning and at the endof systemic treatment a lower dosage (mite) is required, whereas higherdosages (forte) are suitable for a regimen after the initial phase.

In addition to compositions given orally in the form of capsules,granulates and tablets, preparations for cutaneous and transdermaladministration in the form of ointments, plasters, lotions and showercompositions, preparations for parenteral administration in the form ofaqueous micro-dispersions, oil-in-water emulsions or oily solutions,preparations for rectal administration in the form of suppositories ormicro-enemas and preparations for a therapy of hair, finger-nails andtoe-nails by medication are also the subject matter of the invention.

Example 6 Preparation of enteric-coated film-tablets containing 100.0 mgof monomethyl fumarate-Ca salt, which corresponds to 78 mg of fumaricacid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 10.000 kg of monomethyl fumarate calcium salt arecrushed, mixed and homogenised by means of an 800 sieve. Then anexcipient mixture with the following composition is prepared: 21.000 kgof starch derivative (STA-RX 1500®), 2.000 kg of micro-crystallinecellulose (Avicel PH 101®), 0.600 kg of polyvinyl pyrrolidone (PVP,Kollidon® 25) 4.000 kg of Primogel, 0.300 kg of colloidal silicic acid(Aerosil®). The active ingredient is added to the mixture, mixed,homogenised by means of a 200 sieve, processed in the usual manner witha 2% aqueous solution of polyvidon pyrrolidone (Kollidon® K30) to obtaina binder granulate and then mixed in the dry state with the outer phase.Said outer phase consists of 2.000 kg of a so-called FST-complexcontaining 80% of talcum, 10% of silicic acid and 10% of magnesiumstearate. Then the mixture is pressed in the usual manner to obtainconvex tablets having a weight of 400 mg and a diameter of 10 mm.Instead of these classic tabletting methods other methods for preparingtablets such as direct tabletting and solid dispersions according to themelting and spray-drying method may also be used. The application of agastric acid-resistant coating and a film-coat to the tablet cores iscarried out analogously to examples 1 and 4.

Example 7 Preparation of enteric-coated film-tablets containing 50.0 mgof monomethyl fumarate-Ca salt, 50.0 mg of dimethyl fumarate, 5.0 mg ofmonomethyl fumarate-Mg salt and 3.0 mg of monomethyl fumarate-Zn salt,which corresponds to 85 mg of fumaric acid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 5.000 kg of dimethyl fumarate, 5.000 kg of monomethylfumarate-Ca salt, 0.500 kg of monomethyl fumarate-Mg salt and 0.300 kgof monomethyl fumarate-Zn salt are crushed, mixed and homogenised bymeans of an 800 sieve. Then an excipient mixture with the followingcomposition is prepared as described in example 4: 19.000 kg of starchderivative (STA-RX 1500®), 3.000 kg of micro-crystalline cellulose(Avicel PH 101®), 0.750 kg of polyvinyl pyrrolidone (PVP, Kollidon® 120)4.000 kg of Primogel, 0.250 kg of colloidal silicic acid (Aerosil®).

The excipients and the active ingredient are mixed intensely,homogenised by means of a 200 sieve, processed in the usual manner witha 2% aqueous solution of polyvinyl pyrrolidone (PVP, Kollidon® 25) toobtain a binder granulate and then mixed in the dry state with the outerphase. Said outer phase consists of 0.500 kg of magnesium stearate (Ph.Eur.) and 1.500 kg of talcum (Ph. Eur. II).

Then the entire granulate is pressed in the usual manner to obtainconvex tablets having a weight of 400 mg and a diameter of 10 mm.Instead of these classic tabletting methods other methods for preparingtablets such as direct tabletting and solid dispersions according to themelting and spray-drying method may also be used. The application of agastric acid-resistant coating and a film-coat to the tablet cores iscarried out analogously to examples 1 and 4.

Example 8 Preparation of enteric-coated film-tablets containing 50.0 mgof mono-n-propyl fumarate-Ca salt, which corresponds to 32,8 mg offumaric acid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 5.000 kg of mono-propyl fumarate-Ca salt are crushed,mixed and homogenised by means of an 800 sieve. Then an excipientmixture with the following composition is prepared: 25.000 kg of starchderivative (STA-RX 1500®), 3.000 kg of micro-crystalline cellulose(Avicel PH 101®), 0.600 kg of polyvinyl pyrrolidone (PVP, Kollidon® 25),4.000 kg of Primogel, 0.300 kg of colloidal silicic acid (Aerosil®)

The active ingredient is added to the powder mixture, mixed, homogenisedby means of a 200 sieve, processed in the usual manner with a 2% aqueoussolution of polyvidon pyrrolidone (Kollidon® K30) to obtain a bindergranulate and then mixed in the dry state with the outer phase. Saidouter phase consists of 2.000 kg of a so-called FST-complex containing80% of talcum, 10% of silicic acid and 10% of magnesium stearate.

Then the entire granulate is pressed in the usual manner to obtainconvex tablets having a weight of 400 mg and a diameter of 10 mm.Instead of these classic tabletting methods other methods for preparingtablets such as direct tabletting and solid dispersions according to themelting and spray-drying method may also be used. The application of agastric acid-resistant coating and a film-coat to the tablet cores iscarried out analogously to examples 1 and 4.

Example 9 Preparation of gastric-acid resistant pellets in capsulescontaining 50.0 mg of monomethyl fumarate-Ca salt, 5.0 mg of monomethylfumarate-Mg salt and 3.0 mg of monomethyl fumarate-Zn salt, whichcorresponds to 45 mg of fumaric acid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 5.000 kg of monomethyl fumarate-Ca salt, 0.500 kg ofmonomethyl fumarate-Mg salt and 0.300 kg of monomethyl fumarate-Zn saltare crushed, mixed intensely and homogenised by means of a 400 sieve. Atthe same time, 2 l of a 20% (m/V) polyvinyl pyrrolidone (Kollidon K30)solution in ethanol is prepared. 7.250 kg of non-pareilles pellets areplaced in a coating pan and sprayed with part of the Kollidon K30solution until slightly moist. Then the active ingredient mixture isadded in portions until the pellets are dry. This moistening/dryingprocedure is continued until all of the active ingredient mixture hasbeen added. The remainder of the PVP solution is mixed with 0.720 kg ofEudragit E 12.5% solution and sprayed onto the pellets in its entirety.Finally, the pellets are moved around until completely dry. Instead ofthis method, other methods for preparing pellets may also be used, suchas fluidised-bed coating or the extrusion-spherosination method. Inaddition, pellets containing the individual active ingredients may beprepared and then added in appropriate proportions after having beenprovided with a film-coat (see below).

The pellets are sprayed with Eudragit S 12.5% solution and dried withtalcum. After each spraying/drying cycle the release of the activeingredient is measured and the addition of Eudragit S 12.5%solution/talcum continued until the release values meet thespecification.

Then the enteric-coated pellets are filled into capsules (146 mgpellets/capsule).

Example 10 Preparation of gastric-acid resistant capsules containing50.0 mg of mono-iso-propyl fumarate-Ca salt, 50.0 mg of di-iso-propylfumarate, 5.0 mg of mono-iso-propyl fumarate-Mg salt and 3.0 mg ofmono-iso-propyl fumarate-Zn salt, which corresponds to 67 mg of fumaricacid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 5.000 kg of mono-iso-propyl fumarate-Ca salt, 5.000 kgof di-iso-propyl fumarate, 0.500 kg of mono-iso-propyl fumarate-Mg saltand 0.300 kg of mono-iso-propyl fumarate-Zn salt are crushed, mixedintensely and homogenised by means of an 800 sieve. Then a powdermixture with the following composition is mixed into this activeingredient mixture: 32.200 kg of spray-dried lactose, 2.000 kg ofmicro-crystalline cellulose (Avicel) and 1.000 kg of colloidal silicicacid (Aerosil®), 1.000 kg of magnesium stearate and 2.000 kg of talcum.The entire powder mixture is homogenised once more by means of a 200sieve, filled into hard gelatine capsules at a net weight of 500 mg andsaled.

These capsules are then usually provided with a enteric-coated coatingconsisting of hydroxy propyl methyl cellulose phthalate (HPMCP) andcastor oil as softening agent. Instead of hard gelatine capsules, theactive ingredient may also be filled into other gastric acid-resistantcapsules which consist of a mixture of cellulose acetate phthalate (CAP)and hydroxy propyl ethyl cellulose acetate phthalate (HPMCP).

Example 11 Preparation of micro-pellets in capsules containing 50.0 mgof methyl hydrogen fumarate, which corresponds to a total of 44.6 mg offumaric acid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 5.000 kg of methyl hydrogen fumarate are crushed andhomogenised by means of a 400 sieve. In addition, 2 l of a 20% (m/V)polyvinyl pyrrolidone (Kollidon K30) solution in ethanol are prepared.7.250 kg of non-pareilles pellets are placed into a coating pan andsprayed with part of the Kollidon K30 solution until slightly moist.Then the active ingredient mixture is added in portions until thepellets are dry. This moistening/drying cycle is continued until all ofthe active ingredient mixture has been added. Finally, the pellets aremoved around until they are completely dry. Instead of this method, itis also possible to use other methods for preparing pellets, such asfluidised-bed coating and the extrusion/spherosination method. Inaddition, the pellets may also be prepared with the individual activeingredients which are then added in the appropriate proportion afterfilm-coating.

Then the pellets are filled in capsules (126.5 mg of pellets/capsule).

In the following, the effectiveness of the use according to theinvention is shown on the example of the inhibition of haemagglutininformation in an animal experiment and compared with a recognisedmedicament of the prior art:

Investigation of the influence of a formulation according to example 4and of methyl hydrogen fumarate-Ca salt on haemagglutinin formation inmice after peroral administration

By inhibiting the formation of haemagglutinin in mice immuno-suppressiveeffects of certain substances may be shown. This test is based on thedirect haemagglutination where a visible agglutination of erythrocytesoccurs due to specific antibodies directed against the surface antigensof erythrocytes.

Mice are made immune with sheep erythrocytes (day 0). Then the substanceto be tested is applied five times (days 0-4). On the ninth day afterimmunisation, the haemagglutinin levels are determined. A reduction inhaemagglutinin formation shows an immuno-suppressive effect.

It was the objective of these tests to test the effect of a formulationaccording to example 4 and of methyl hydrogen fumarate-Ca salt on thehaemagglutinin formation in mice after peroral administration of 150,300 and 600 mg/kg, respectively.

In this experiment, it was possible to show the dosage-dependentsuppressive effect of the formulation on the basis of the proportions ofthe active ingredients according to example 4 on haemagglutininformation in mice. The effect of a total dose of 300 mg/kg of saidformulation (application of the combination of active ingredients in a0.8% suspension in aqueous HPMC of gel-like consistence) was still inthe normal range of deviation, whereas a reproducible 29% inhibition ofhaemagglutinin formation could be shown after administration of 600mg/kg of the above formulation.

A dosage-dependent suppressive effect on haemagglutinin formation inmice could also be shown for methyl hydrogen fumarate-Ca salt. A dosageof 300 mg/kg of methyl hydrogen fumarate-Ca salt caused a slightreduction of haemagglutinin formation, whereas a reproducible 38%inhibition of haemagglutinin formation could be shown afteradministration of 600 mg/kg methyl hydrogen fumarate-Ca salt.

For comparison, an analogous experiment was carried out in a dosagerange of 150, 200 and 300 mg/kg of cyclosporin A. The dosage range wasselected in accordance with J. B. Borel et al., Biological Effects ofCyclosporin A: A New Antilymphotic Agent, Biological and MedicalResearch Division, Sandoz Ltd., CH-4002 Basle, Switzerland; Agents andActions, 6/4, 468-475 (1975). For cyclosporin, a 37% reduction inhaemagglutinin formation could be shown at a dosage of 150 mg/kg. At amaximum dosage of 300 mg/kg of cyclosporin, a 59% inhibition ofhaemagglutinin formation was achieved.

The results of these investigations permit the conclusion that both aformulation according to example 4 and methyl hydrogen fumarate-Ca saltexercise a significant immuno-suppressive effect.

Among other things, the immuno-suppressive effect of cyclosporin iscaused by an inhibition of Th-1 cell formation. As in vitro experimentshave shown, fumarates cause a shift in the cytokin pattern from the Th1to the Th2 type.

If the findings of both the in vivo and the in vitro experiments areviewed together, a meaningful and unexpectedly improved use of fumaratesin transplantation medicine, especially with regard to a long-termmaintnance therapy results.

Investigation of the influence of a formulation according to example 4and methyl hydrogen fumarate-Ca salt after peroral administration onhaemagglutinin formation in mice

Reduction of serum haemagglutinin formation in mice

Proportion of the Inhibition of mg/kg bodyweight serum titres con-Suppression haemagglutinin p.o. trol/verum group index formation in %Combination of active ingredi- ents as in example 4 150 10.7/12.8 0.8416 300 10.8/12.8 0.84 16 600  9.1/12.8 0.71 29 Methyl hydrogenfumarate-Ca salt 150 11.1/12.8 0.87 13 300 10.2/12.8 0.80 20 600 7.9/12.8 0.62 38 Cyclosporin A 150  8.0/12.8 0.63 37 200  7.1/12.8 0.5545 300  5.3/12.8 0.41 59 p.o. = administered perorally

Haemagglutinins

Designation for substances causing haemagglutination, especiallyagglutinating antibodies, phythaemagglutinins, generally haemagglutininsformed by virus infection (measles, mumps, rubella, influenza,arboviroses) and surface antigens of certain virus types.

Haemagglutination

Visible agglutination of erythrocytes caused by haemagglutinins; asdirect (active) haemagglutination caused by antibodies directedspecifically against surface antigens of the erythrocytes or as indirect(passive) haemagglutination after loading erythrocytes with an antigen(e.g. Vi-antigen in typhus-Vi-haemagglutination, globulin in ananti-globulin test) caused by antibodies directed specifically againstthe relevant antigen. The strength of a haemagglutination (for examplein a serological titration of a haemagglutinating anti-serum) isreported by a numeral (dilution stage of the serum tested where ahaemagglutination can only just be detected).

Compared to a therapy with substances of the prior art such ascyclosporin which may cause severe kidney disorders or diseases of thelymphoproliferative system, treatment with fumaric acid derivativesaccording to the indications as per the invention will cause onlytemporary disorders and will rarely have severe side effects [cf. DMW(German Weekly Medical Magazine), 121 (1996) pages 1605-1607].Especially in view of the necessary long-term therapy and prevention ofgraft-versus-host reactions or multiple sclerosis this unexpected effectof the use according to the invention is of the highest interest.Combination therapy of cyclosporin with the fumaric acid derivativeswill reduce the toxic side effects of the former compounds dramaticallyand unexpectedly. Moreover, the use according to the invention is alsoof major significance in the substitution of a corticoid therapy which,as is generally known, has severe side effects.

The terms and expressions which have been employed are used as terms ofdescription and not of limitation, and there is no intention in the useof such terms and expressions of excluding any equivalent of thefeatures shown and described or portions thereof, it being recognizedthat various modifications are possible within the scope of theinvention.

What is claimed is:
 1. A method for treating a patient suffering from anauto immune disease selected from the group consisting of graft-versushost reactions, juvenile diabetes, Hashimoto's thyroiditis, Grave'sdisease, systemic Lupus erythematosus (SLE), Sjogren's syndrome,pernicious anaemia and chronically active (=lupoid) hepatitiscomprising: administering an effective amount of a compound of a sodium,potassium, calcium, magnesium, zinc or iron salt of a funaric acidmonoalkyl ester of the general formula

optionally in combination with dialkyl fumarate of the formula wherein Ais a bivalent cation selected from the group consisting of Ca, Mg, Zn orFe or a monovalent cation from the series consisting of potassium orsodium, respectively, and n denotes the numeral 1 or 2 depending on thetype of cation, or administering at least one alkyl hydrogen fumaratecompound of the general formula optionally in combination with dialkylfumarate of the formula wherein each of R, R₁ and R₂ is C₁-C₅ alkyl andmay be the same or different; and optionally, in combination withcommonly used pharmaceutical excipients and vehicles.
 2. The method ofclaim 1, wherein the calcium salt of the fumaric acid monoethyl ester isadministered.
 3. The method of claim 1, wherein the calcium salt of thefumaric acid monomethyl ester is administered.
 4. The method of claim 1,wherein the calcium salt of the fumaric acid monoethyl ester inadmixture with dimethyl fumarate is administered.
 5. The method of claim1, wherein the calcium and zinc salts of the fumaric acid monoethylester in admixture with dimethyl fumarate are administered.
 6. Themethod of claim 1, wherein a mixture of calcium, magnesium and zinc saltof the fumaric acid monoethyl ester in admixture with dimethyl fumarateis administered.
 7. The method of claim 1, wherein the method fortreating comprises oral administration in the form of tablets orcapsules, said tablets or capsules comprising the calcium salt of thefumaric acid monoalkyl ester in an amount of 10 to 300 mg, the totalweight of the active ingredients being 10 to 300 mg.
 8. The method ofclaim 1, wherein the method for treating comprises oral administrationin the form of tablets or capsules, said tablets or capsules comprising10 to 290 parts by weight of the calcium salt of the fumaric acidmonoalkyl ester and 290 to 10 parts by weight of dimethyl fumarate, thetotal weight of the active ingredients being 20 to 300 mg.
 9. The methodof claim 1, wherein the method for treating comprises oraladministration in the form of tablets or capsules, said tablets orcapsules comprising 10 to 250 parts by weight of the calcium salt of thefumaric acid monoalkyl ester, 1 to 50 parts by weight of dimethylfumarate and 1 to 50 parts by weight of the zinc salt of the fumaricacid monoalkyl ester, the total weight of the active ingredients being20 to 300 mg.
 10. The method of claim 1, wherein the method for treatingcomprises oral administration of a pharmaceutical composition in theform of tablets or capsules comprising 10 to 250 parts by weight of thecalcium salt of the fumaric acid monoalky ester, 250 to 10 parts byweight of dimethyl fumarate, 1 to 50 parts by weight of the magnesiumsalt of the fumaric acid monoalkyl ester and 1 to 50 parts by weight ofthe zinc salt of the fumaric acid monoalkyl ester, the total weight ofthe active ingredients being 30 to 300 mg.
 11. The method of claim 1,further comprising a sequential or alternating administration ofcyclosporin.
 12. The method of claim 1, wherein the compound iscontained in pellets or microtablets having a mean diameter,respectively, in the range of 300 to 2,000 μm, especially in the rangeof 500 μm to 1,500 μm or 1,000 μm.
 13. The method of claim 1, whereinthe compound is administered as a medicament in the form of tablets,soft or hard gelatine capsules, granules, micro-tablets and in the formof preparations which may be applied by topical, parenteral and rectalroutes.
 14. The method for claim 1, wherein the dosage unit of themedicament is coated with a gastric acid resistant coating.
 15. A methodfor treating a patient suffering from an auto immune disease selectedfrom the group consisting of polyarthritis, multiple sclerosis andgraft-versus host reactions, juvenile diabetes, Hashimoto's thyroiditis,Grave's disease, systemic Lupus erythematosus (SLE), Sjogren's syndrome,pernicious anaemia and chronically active (=lupoid) hepatitiscomprising: administering in the form of pellets or microtablets aneffective amount of a compound of a sodium potassium, calcium,magnesium, zinc or iron salt of a fumaric acid monoalkyl ester of thegeneral formula: optionally in combination with dialkyl funarate of theformula wherein A is a bivalent cation selected from the groupconsisting of Ca, Mg, Zn or Fe or a monovalent cation from the seriesconsisting of potassium or sodium, respectively, and n denotes thenumeral 1 or 2 depending on the type of cation, or administering atleast one alkyl hydrogen fumarate compound of the general formulaoptionally in combination with dialkyl fumarate of the formula whereineach of R, R₁ and R₂ is C₁-C₅ alkyl and may be the same or different.16. The method of claim 15, wherein the calcium salt of the fumaric acidmonoethyl ester is administered.
 17. The method of claim 15, wherein thecalcium salt of the fumaric acid monomethyl ester is administered. 18.The method of claim 15, wherein the calcium salt of the fumaric acidmonoethyl ester in admixture with dimethyl fumarate is administered. 19.The method of claim 15, wherein the calcium and zinc salts of thefumaric acid monoethyl ester in admixture with dimethyl fumarate areadministered.
 20. The method of claim 15, wherein a mixture of calcium,magnesium and zinc salts of the fumaric acid monoethyl ester inadmixture with dimethyl fumarate is administered.
 21. The method ofclaim 15, further comprising a sequential or alternating administrationof cyclosporin.
 22. The method of claim 15, wherein the dosage unit ofthe medicament is coated with a gastric acid resistant coating.
 23. Themethod of claim 15, wherein the size of the microtablets or pellets isin the range of 300 μm to 200 μm.